Urethral Cancer Treatment (PDQ®)

Last Modified : 2015-10-02

General Information About Urethral Cancer

Incidence and Mortality

Urethral cancer is rare. The annual incidence rates in the Surveillance, Epidemiology, and End Results database over the period from 1973 to 2002 in the United States for men and for women were 4.3 and 1.5 per million, respectively, with downward trends over the three decades.
[1]
The incidence was twice as high in African Americans as in whites (5 million vs. 2.5 per million). Urethral cancers appear to be associated with infection with human papillomavirus (HPV), particularly HPV16, a strain of HPV known to be causative for cervical cancer.
[2]
[3]

Because of its rarity, nearly all information about the treatment of urethral cancer and the outcomes of therapy is derived from retrospective, single-center case series and, therefore, represents a very low level of evidence of 3iiiDiv. The majority of information comes from cases accumulated over many decades at major academic centers.

Anatomy

The female urethra is largely contained within the anterior vaginal wall. In adults, it is about 4 cm in length.

The male urethra, which averages about 20 cm in length, is divided into distal and proximal portions. The distal urethra, which extends distally to proximally from the tip of the penis to just before the prostate, includes the meatus, the fossa navicularis, the penile or pendulous urethra, and the bulbar urethra. The proximal urethra, which extends from the bulbar urethra to the bladder neck, includes distally to proximally the membranous urethra and the prostatic urethra.

Anatomy of the male urinary system (left panel) and female urinary system (right panel) showing the kidneys, ureters, bladder, and urethra. Urine is made in the renal tubules and collects in the renal pelvis of each kidney. The urine flows from the kidneys through the ureters to the bladder. The urine is stored in the bladder until it leaves the body through the urethra.

Prognosis

The prognosis of urethral cancer depends on the following factors:
[4]
[5]
[6]

Anatomical location.

Size.

Stage.

Depth of invasion.

Superficial tumors located in the distal urethra of both
the female and male are generally curable. However, deeply invasive lesions are rarely curable by any combination of therapies.
In men, the prognosis of tumors in the distal (pendulous) urethra is better than for tumors of the proximal (bulbomembranous) and prostatic urethra, which tend to present at more advanced stages.
[7]
[8]
Likewise, distal urethral tumors tend to occur at earlier stages in women, and they appear to have a better prognosis than proximal tumors.
[9]

The female urethra is lined by transitional cell mucosa proximally and
stratified squamous cells distally. Therefore, transitional cell carcinoma is most common in the proximal urethra and squamous cell carcinoma predominates
in the distal urethra. Adenocarcinoma may occur in both locations and arises
from metaplasia of the numerous periurethral glands.

The male urethra is lined by transitional cells in its prostatic and membranous
portion and stratified columnar epithelium to stratified squamous epithelium in
the bulbous and penile portions. The submucosa of the urethra contains
numerous glands. Therefore, urethral cancer in the male can manifest the
histological characteristics of transitional cell carcinoma, squamous cell
carcinoma, or adenocarcinoma.

Except for the prostatic urethra, where transitional cell carcinoma is most
common, squamous cell carcinoma is the predominant histology of urethral
neoplasms. Since transitional cell carcinoma of the prostatic urethra may be associated with transitional cell carcinoma of the bladder and/or
transitional cell carcinoma arising in prostatic ducts, it is often treated similarly to these primaries and should be separated from
the more distal carcinomas of the urethra.

Stage Information for Urethral Cancer

The histology of the
primary tumor is of less importance in estimating response to therapy and
survival.
[2]
Endoscopic examination, urethrography, and magnetic resonance imaging are useful in determining the local extent of the tumor.
[3]
[4]

Distal Urethral Cancer

These lesions are often superficial.

Female: Lesions of the distal third of the urethra.

Male: Anterior, or penile, portion of the urethra, including the meatus and
pendulous urethra.

Proximal Urethral Cancer

These lesions are often deeply invasive.

Female: Lesions not clearly limited to the distal
third of the urethra.

Male: Bulbomembranous and prostatic urethra.

Urethral Cancer Associated with Invasive Bladder Cancer

Approximately 5% to 10% of men with cystectomy for bladder cancer may have or may develop urethral cancer distal to the urogenital diaphragm.
[5]
[6]

Stage Definitions by Depth of Invasion

Stage 0 (Tis, Ta): Limited to mucosa.

Stage A (T1): Submucosal invasion.

Stage B (T2): Infiltrating periurethral muscle or corpus spongiosum.

Stage C (T3): Infiltration beyond periurethral tissue.

Female: Vagina, labia, muscle.
Male: Corpus cavernosum, muscle.

Stage D1 (N+): Regional nodes; pelvic and inguinal.

Stage D2 (N+, M+): Distant nodes; visceral metastases.

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM
classification to define urethral cancer.
[1]

Treatment Option Overview

Information about the treatment of urethral cancer and the outcomes of therapy is derived from retrospective, single-center case series and represents a very low level of evidence of 3iiiDiv. The majority of this information comes from the small numbers of cases accumulated over many decades at major academic centers. Therefore, the treatment in these reports is usually not standardized and the treatment also spans eras of shifting supportive care practices. Because of the rarity of urethral cancer, its treatment may also reflect extrapolation from the management of other urothelial malignancies, such as bladder cancer in the case of transitional cancers, and anal cancer in the case of squamous cell carcinomas.

Role of Surgery

Surgery is the mainstay of therapy for urethral cancers in both women and men.[Level of evidence: 3iiiDiv] The surgical approach depends on tumor stage and anatomic location, and tumor grade plays a less important role in treatment decisions.
[1]
[2]
Although the traditional recommendation has been to achieve a 2-cm tumor-free margin, the optimal surgical margin has not been rigorously studied and is not well defined. The role of lymph node dissection is not clear in the absence of clinical involvement, and the role of prophylactic dissection is controversial.
[2]
Radiation therapy and/or chemotherapy may be added in some cases in patients with extensive disease or in an attempt at organ preservation; but there are no clear guidelines for patient selection, and the low level of evidence precludes confident conclusions about their incremental benefit.
[2]
[3]

Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporization-coagulation, are used to preserve organ function in cases of superficial anterior tumors, although the supporting literature is scant.
[2]

Role of Radiation Therapy

Radiation therapy with external beam, brachytherapy, or a combination is sometimes used for the primary therapy of early-stage proximal urethral cancers, particularly in women.[Level of evidence: 3iiiDiv] Brachytherapy may be delivered with low-dose-rate iridium-192 sources using a template or urethral catheter. Definitive radiation is also sometimes used for advanced-stage tumors, but because monotherapy of large tumors has shown poor tumor control, it is more frequently incorporated into combined modality therapy after surgery or with chemotherapy.
[4]
There are no head-to-head comparisons of these various approaches, and patient selection may explain differences in outcomes among the regimens.[Level of evidence: 3iiiDiv]

The most commonly used tumor doses are in the range of 60 Gy to 70 Gy. Severe complication rates for definitive radiation are about 16% to 20% and include fistula development, especially for large tumors invading the vagina, bladder, or rectum. Urethral strictures also occur in the setting of urethral-sparing treatment. Toxicity rates increase at doses greater than 65 Gy to 70 Gy. Intensity-modulated radiation therapy has come into more common use in an attempt to decrease local morbidity of the radiation.
[4]

Role of Chemotherapy

The literature on chemotherapy for urethral carcinoma is anecdotal in nature and restricted to retrospective, single-center case series or case reports.
[5]
[Level of evidence: 3iiiDiv] A wide variety of agents used alone or in combination have been reported over the years, and their use has largely been extrapolated from experience with other urinary tract tumors.

For squamous cell cancers, agents that have been used in penile cancer or anal carcinoma include:
[3]
[5]

Chemotherapy has been used alone for metastatic disease or in combination with radiation therapy and/or surgery for locally advanced urethral cancer. It may be used in the neoadjuvant setting with radiation therapy in an attempt to increase the resectability rate or in an attempt at organ preservation.
[3]
However, the impact of any of these regimens on survival is not known for any stage or setting.

Distal Urethral Cancer

Female Distal Urethral Cancer

If the malignancy is at or just within the meatus and superficial parameters (stage 0/Tis,
Ta), open excision or electroresection and fulguration may be possible. Tumor
destruction using Nd:YAG or CO2 laser vaporization-coagulation represents an
alternative option. For large lesions and more invasive lesions (stage A and stage B,
T1 and T2, respectively), brachytherapy or a combination of brachytherapy and
external-beam radiation therapy are alternatives to surgical resection of the distal third of
the urethra. Patients with T3 distal urethral lesions, or lesions that recur after treatment with
local excision or radiation therapy, require anterior
exenteration and urinary diversion.

If inguinal nodes are palpable, frozen section confirmation of tumor should be
obtained. If positive for malignancy, ipsilateral node dissection is indicated. If no
inguinal adenopathy exists, node dissection is not generally performed, and the nodes are followed clinically.

External-beam radiation therapy, brachytherapy, or a combination of the two (T1, T2 lesions).
[4]

Anterior exenteration with or without preoperative radiation and diversion
(T3 lesions or recurrent lesions).
[2]
[3]

The level of evidence for these treatment options is 3iiiDiv.

Male Distal Urethral Cancer

If the malignancy is in the pendulous urethra and is superficial, there is potential
for long-term disease-free survival. In the rare cases that involve mucosa only (stage 0/Tis, Ta),
resection and fulguration may be used. For infiltrating
lesions in the fossa navicularis, amputation of the glans penis may be adequate
treatment. For lesions involving more proximal portions of the distal urethra,
excision of the involved segment of the urethra, preserving the penile corpora,
may be feasible for superficial tumors. Penile amputation is used for infiltrating lesions. Traditionally, a 2-cm margin proximal to the tumor is used, but the optimal margin has not been well studied. Local recurrences after amputation
are rare.

The role of radiation therapy in the treatment of anterior urethral
carcinoma in the male is not well defined. Some anterior urethral cancers have
been cured with radiation alone or a combination of chemotherapy and radiation therapy.
[4]
[5]

If inguinal nodes are palpable, ipsilateral node dissection is indicated after
frozen section confirmation of tumor, because cure is still achievable with limited
regional nodal metastases. If no inguinal adenopathy exists, node dissection
is not generally performed, and the nodes are followed clinically.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
distal urethral cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Proximal Urethral Cancer

Female Proximal Urethral Cancer

Lesions of the proximal or entire length of the urethra are usually associated with invasion
and a high incidence of pelvic nodal metastases. The prospects for cure are
limited except in the case of small tumors. The best results have been
achieved with exenterative surgery and urinary diversion with 5-year survival rates
ranging from 10% to 20%.

To increase the resectability rate of gross tumor and decrease local recurrence, in an effort to shrink tumor margins, it is reasonable to recommend adjunctive, preoperative, radiation
therapy. Pelvic
lymphadenectomy is performed concomitantly. Ipsilateral inguinal node dissection is
indicated only if biopsy specimens of ipsilateral palpable adenopathy are positive on
frozen section. For tumors that do not exceed 2 cm in greatest
dimension, radiation alone, nonexenterative surgery alone, or a combination
of the two may be sufficient to provide an excellent outcome.

It is reasonable to consider removal of
part of the pubic symphysis and the inferior pubic rami to maximize the
surgical margin and reduce local recurrence. The perineal closure
and vaginal reconstruction can be accomplished with the use of myocutaneous
flaps.

The prognosis of female urethral cancer is related to the size of the
lesion at presentation. For lesions less than 2 cm in diameter, a 60%
5-year survival can be anticipated; for those greater than 4 cm in
diameter, the 5-year survival falls to 13%.

Standard treatment options:

Preoperative radiation followed by anterior exenteration and urinary
diversion with bilateral pelvic node dissection with or without inguinal node
dissection.
[1]

For tumors that do not exceed 2 cm in greatest dimension,
radiation alone, nonexenterative surgery alone, or the combination may be
sufficient to provide an excellent outcome.
[1]
[2]

The level of evidence for these treatment options is 3iiiDiv.

Male Proximal Urethral Cancer

Lesions of the bulbomembranous urethra require radical cystoprostatectomy and
en bloc penectomy to achieve adequate margins of resection, minimize local
recurrence, and achieve long-term, disease-free survival. Pelvic lymphadenectomy is also performed because of the high incidence of positive nodes and the limited added
morbidity.

Despite extensive surgery, local recurrence is common, and this event is invariably associated with eventual death from
the disease. Five-year survival can be expected in only 15% to 20% of patients.
In an effort to shrink tumor margins, the use of preoperative adjunctive
radiation therapy may be considered. In an effort to increase the surgical
margins of dissection, resection of the inferior pubic rami and the lower
portion of the pubic symphysis has been used. Urinary diversion is
required.
[3]

Ipsilateral inguinal node dissection is indicated if palpable ipsilateral
inguinal adenopathy is found on physical examination and confirmed to be
neoplasm by frozen section.

Standard treatment options:

Preoperative radiation or combined chemotherapy and radiation therapy followed by cystoprostatectomy, urinary diversion, and
penectomy with bilateral pelvic node dissection with or without inguinal node
dissection.
[4]

The level of evidence for these treatment options is 3iiiDiv.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
proximal urethral cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Urethral Cancer Associated With Invasive Bladder Cancer

Approximately 10% (range, 4%–17%) of patients who undergo cystectomy for bladder cancer can be
expected to have or to later develop clinical neoplasm of the urethra distal to
the urogenital diaphragm.
Factors associated with the risk of urethral recurrence after cystectomy include:
[1]
[2]

Tumor multiplicity.

Papillary pattern.

Carcinoma in situ.

Tumor location at the bladder neck.

Prostatic urethral mucosal or stromal involvement.

The benefits of urethrectomy at the time of cystectomy need to be weighed
against the morbidity factors, which include added operating time, hemorrhage, and the
potential for perineal hernia. Tumors found incidentally on
pathologic examination are much more likely to be superficial or in situ in
contrast to those that present with clinical symptoms at a later date when
the likelihood of invasion within the corporal bodies is high. The former
lesions are often curable, and the latter are only rarely so. Indications for
urethrectomy in continuity with cystoprostatectomy are:

Visible tumor in the urethra.

Positive swab cytology of the urethra.

Positive margins of the membranous urethra on frozen section taken at the
time of cystoprostatectomy.

Recurrent or Metastatic Urethral Cancer

Local recurrences of urethral cancer may be amenable to local modality therapy with radiation or surgery, with or without chemotherapy. (Refer to the Treatment Option Overview section of this summary for more information.) Metastatic disease may be treated with regimens in common use for other urothelial transitional cell or squamous cell carcinomas, or anal carcinomas, depending upon the histology.
[1]
[2]
[3]

Treatment options:

Locally recurrent urethral cancer after radiation therapy should be treated
by surgical excision, if feasible.

Locally recurrent urethral cancer after surgery alone should be considered
for combination radiation and wider surgical resection.

Metastatic urethral cancer should be considered for clinical trials using chemotherapy. Transitional cell cancer of the urethra may respond favorably to the same chemotherapy regimens employed for advanced transitional cell cancer of the bladder.
[1]
[2]
[3]
[4]

The level of evidence for these treatment options is 3iiiDiv.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
recurrent urethral cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of urethral cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Urethral Cancer Treatment is:

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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